San Francisco 49ers vs. Arizona Cardinals Prediction, Preview, and Odds

Arizona and San Francisco will play in Mexico City on Monday Night Football, pitting a 5-4 Niners squad against a 4-6 Cardinals unit. The 49ers are 3-2 over their past five and have won consecutive games. The Cardinals are 2-3 over the same span after defeating the Rams last week at home. Kickoff from Estadio Azteca will be at 8:15 pm EDT. San Francisco is an eight-point spread favorite, and the game total is 43.5 points.

San Francisco has a flashy offense and gritty defense

The 49ers are hot, with consecutive wins over the LA teams and first place in the NFC West within their reach. San Francisco’s offense is legit, with a few star playmakers that attract a lot of attention in Brandon Aiyuk (567 receiving yards and 4 TDs), Deebo Samuel (576 all-purpose yards and 3 TDs), George Kittle (340 receiving yards and 2 TDs), Elijah Mitchell (18 carries for 89 yards vs. LAC), and Christian McCaffrey (288 all-purpose yards and 3 TDs with SF). Aiyuk, Samuel, and Kittle have been reinvigorated by Mitchell’s return from an MCL sprain and McCaffrey’s arrival via trade, giving quarterback Jimmy Garoppolo a stacked deck.

Yet, last week versus the Chargers, the defense led the way. San Francisco kept Los Angeles off the scoreboard in the second half, the second straight game it has done so. Instead of collapsing, SF has rallied since surrendering 44 points to Kansas City in week 8, and the results are clear as day.

“We know that we’re one of the best defenses in the league,” linebacker Fred Warner said. “We’ve shown that throughout the season. One bad game doesn’t define you.”

This season, the Niners are ranked first in total yards allowed, second in rushing yards allowed, eighth in passing yards allowed, and fourth in points allowed per game. The defense has tallied 29 sacks, too, led by Nick Bosa (9 sacks and 11 tackles for loss). San Francisco’s 26 takeaways rank as the 8th-most in the NFL, as well.

It’s time for Arizona to put up or shut up

Arizona is living its worst nightmare with quarterbacks Kyler Murray and Colt McCoy both questionable for Monday Night Football. McCoy started in place of Murray against the Rams last week and exited the game with a knee injury. No matter who starts under center β€” ex-Penn State QB Trace McSorley is next in line β€” Arizona needs them to manage the game with care, especially against a lockdown San Francisco defense.

The 36-year-old McCoy performed admirably in Murray’s absence, throwing for 236 yards, including a touchdown pass to AJ Green. He also connected with DeAndre Hopkins and Rondale Moore often, hitting Hopkins 10 times for 98 yards and Moore nine times for 94 yards. McCoy targeted Hopkins or Moore on 27 of his 37 passing attempts. The Cardinals were also able to rely on running back James Conner, who rushed for 69 yards and two touchdowns. Unfortunately for AZ, tight end Zach Ertz (47 receptions for 406 yards and 4 TDs this season) suffered a knee injury in the first quarter that will leave him out for the rest of the year.

The Cardinals’ defense has not been of much help this season, surrendering 25.8 points per game (30th in the NFL) and 357.6 total yards per game (23rd). Arizona has 19 sacks, 8th-fewest in the league, and is 28th in red zone defense, as its opponents are scoring touchdowns on 67.5 percent of their red zone trips. While the Cardinals are top-ten in rushing yards surrendered (110.5 per game), they’re 23rd against the pass (247.1 yards allowed per game). Furthermore, defensive backs Budda Baker (team-leading 75 tackles) and Byron Murphy Jr. are questionable to play Monday with injury designations.

Best Bets for this Game

Full-Game Side Bet

Insiders Status:


The 49ers own the matchup edge in most statistical categories and are 5-0 ATS in their last five versus the NFC West. San Francisco is also healthy at quarterback, ensuring it will get the most out of its dynamic group of receivers. Arizona boasts several talented stars on offense too, but will it be able to say the same about its quarterback? It’s too bad we won’t see the best of both teams in what should be a lively setting in Mexico City. That said, at the end of the day, we’re here to pick winners.

If I were picking the straight-up winner, it would be San Francisco. However, with an eight-point spread, it’s not as simple. The Niners are 1-7-1 ATS in their last nine meetings with the Cardinals and laid eggs against Atlanta and Kansas City in recent games. While it’s one thing to lose to KC, the 14-point loss to ATL is looking worse with each passing week, as the Falcons are 1-3 since that victory. To keep the score close, Murray or McCoy needs to play and not be too limited to make a difference. Since I believe one of those two will be healthy enough to start, I expect this to be a one-score game.

My bet: Arizona at +7.5 or better.

Prediction: Arizona +8

Full-Game Total Pick

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The under is 9-1 in the Cardinals’ last ten Monday games and 6-1 in the 49ers’ last seven games following a straight-up win. I’ll bet that Murray or McCoy is available for Arizona, but there’s a difference between playing and competing at full health. Whichever QB starts, they will face a vaunted defense capable of causing terror from start to finish. Making a hobbled passer unsettled when he’s in the pocket is enough to force him into a few poor decisions.

As for the 49ers, it’s not as if Joe Montana is leading the offense. Jimmy G is comfortable managing a talented team, but he’s not a difference-maker. Furthermore, even with its weapons, SF is scoring just 22.0 points per game, the 18th-most in the league. That’s at least partially because the Niners are only scoring touchdowns in 54.8 percent of their red zone trips, slightly better than Carolina and Jacksonville. That’s the middle of the pack, ranking 17th out of 32 NFL teams.

Will all this in mind, I’m leaning towards the under at 43.5 points.

Prediction: Under 43.5

Written By
Michael Briggs, “Michael Briggs”

Mike Briggs is a passionate sports fan and writer, earning his BA in Journalism. In 2020, he moved across the country from New Jersey to San Diego to satisfy his lifelong obsession of living near an MLB stadium. As a proud MSU basketball supporter, Mike believes he’s learned a lot watching coach Tom Izzo lead the Spartans to Big Ten titles and Final Fours regularly. He’s also well-read on the NBA, having a subscription to SLAM magazine, the famous “basketball bible,” since he was a teenager. Mike spends his free time strategizing futures bets and researching opportunities to make a few bucks on tonight’s game. You can follow Mike on Twitter @BriggsWrites for sports betting, DFS, and stock trading tips.

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